DENVER—Dual-targeted therapy has emerged as a promising approach for inflammatory bowel disease when the limits of monotherapies may have been reached, but more evidence on the safety and efficacy of this approach is needed, according to presentations at the 2023 annual Crohn’s & Colitis Congress.
There are several settings in which the use of dual-targeted therapy—combinations of anti–tumor necrosis factor (anti-TNF), anti-integrin, interleukin (IL)-23 inhibitor, sphingosine-1-phosphate inhibitor and Janus kinase inhibitor agents—can be beneficial, such as for patients with severe and high-risk presentations, meaningful but incomplete responses to treatment, or unique phenotypes, noted Laura Targownik, MD, MSHS, FRCPC, an associate professor of medicine and the director of the Division of Gastroenterology and Hepatology at the University of Toronto. However, safety concerns and increased costs are disadvantages of dual-targeted therapy, she said. In addition, recent trials have shown that most patients do not achieve the desired outcomes, even with the best therapies, Dr. Targownik said.
Discussing the literature supporting this treatment strategy and the research needed to move the field forward, Dr. Targownik stressed that it is important to understand the drugs’ mechanisms of action to employ combinations in which the drugs enhance each other’s anti-inflammatory effects and avoid combinations that are mediated through a common pathway and might not offer enhanced benefit.
Limited High-Quality Data
In the VEGA study (ClinicalTrials.gov Identifier: NCT03662542), investigators evaluated the efficacy of dual-targeted therapy with anti-TNF agent golimumab (Simponi, Janssen) and the IL-23 inhibitor guselkumab (Tremfya, Janssen) in patients with moderate to severe ulcerative colitis. The study included 214 patients who were randomly assigned to receive golimumab alone, guselkumab alone or a combination of both during the induction phase. After the induction phase, patients were followed for 38 weeks in the maintenance phase.
Results of the study showed that the combination therapy led to significantly higher rates of clinical remission and endoscopic normalization compared with monotherapy. However, these rates were still lower than those seen in other studies of single agents, and the results were only observed over 26 weeks. So, the long-term effectiveness of the combination therapy is unknown, Dr. Targownik noted.
The open-label, single-arm EXPLORER-CD study (ClinicalTrials.gov Identifier: NCT02764762) looked at the combination of the anti-integrin agent vedolizumab (Entyvio, Takeda), the anti-TNF agent adalimumab and methotrexate in a high-risk population with early-stage, active Crohn’s disease. The study included 55 participants who were diagnosed within 24 months of enrollment and had a simple endoscopic score for Crohn’s disease (SES-CD) of 7 or higher and isolated ileal disease with a score of 4 or more.
An interim analysis showed that 54.5% of the patients achieved clinical remission and 34.5% achieved endoscopic remission. There was a significant improvement in SES-CD scores (from 12.8 to 3.9) and clinical disease activity index scores (from 257.2 to 80.1). However, enrollment of patients was difficult in this open-label trial, Dr. Targownik said, and it is uncertain if a randomized controlled trial of this combination will be conducted.
Relying on Real-World Data
Real-world studies have demonstrated similar results across trials, but the confidence intervals are wide and overlapping, making it impossible to make comparative statements about the superiority of any one combination, according to a systematic review and meta-analysis (Crohns Colitis 360 2022;4[1]:otac002). The side effect profile of the combinations also was a concern, with significant potential for serious adverse events, although there was no increase in major serious events reported in anecdotal accounts of patients’ experiences.
However, since “future randomized controlled trials in dual therapy for IBD will likely be limited, given costs and risks and the need for cooperation between different companies,” Dr. Targownik predicted that answers to the question of the efficacy of dual therapy will likely come from ongoing real-world experiences, with a focus on identifying patient phenotypes and cataloging their experiences with defined outcomes and follow-up. Treatment “decisions will be informed by increasing knowledge about personalization, better ability to identify high-risk patients and the development of a prospective registry.”
More Combination Rx Expected
Despite some of the practical concerns Dr. Targownik mentioned, Edward V. Loftus Jr., MD, the Maxine and Jack Zarrow Family Professor of Gastroenterology at Mayo Clinic, in Rochester, Minn., remained confident about the future of dual-targeting therapy in clinical practice.
“Despite the lack of data in severe high-risk patients receiving dual-targeted therapy up front, the concept of combining medications for specific targets of action is intriguing and shows promise for efficacy,” Dr. Loftus said in a separate presentation at the conference. “Early reports and ongoing clinical trials, such as VEGA and EXPLORER, are shedding light on the potential benefits of combining biologics,” he said.
“With the growing accumulation of data and the emergence of pharmaceutical companies with multiple assets, we can expect to see an increase in combination therapy,” Dr. Loftus said, but he acknowledged that “the practicality of implementing dual-targeted therapy in clinical practice, with insurance and logistical challenges, remains to be seen.”
—Chase Doyle
Dr. Loftus reported financial relationships with AbbVie, Alvotech, Amgen, Arena, Boehringer Ingelheim, BMS, CALIBR, Celgene/Receptos, Celltrion, Fresenius Kabi, Genentech, Gilead, Gossamer Bio, GSK, Iterative Scopes, Janssen, Lilly, Morphic, Ono Pharma, Pfizer, Protagonist, Scipher, Sun Pharma, Surrozen, Takeda, Theravance and UCB. Dr. Targownik reported financial relationships with AbbVie, Amgen, BMS, Fresenius Kabi, GoodCap, Janssen, Organon, Pfizer, Roche, Takeda and Viatris.
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